GABAB Receptors and Alcohol Use Disorders: Preclinical Studies

Holtyn, August F.; Weerts, Elise M.

doi:10.1007/7854_2020_178

Cited by 23 publications

(12 citation statements)

References 97 publications

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“…The results of the two 'alcohol' experiments indicate that treatment with the selective GABA B receptor antagonist, SCH 50911, reduced in a dose-related manner mean lever-responding for alcohol and mean amount of self-administered alcohol in alcohol-preferring sP rats trained to lever-respond for alcohol under the standard FR schedule of reinforcement. Taking into account the multiple lines of experimental evidence indicating that GABA B receptor agonists (see Colombo and Gessa, 2018;Holtyn and Weerts, 2020) and PAMs (see Maccioni and Colombo, 2019;Holtyn and Weerts, 2020) inhibit lever-responding for alcohol, these results extend to alcohol self-administration the notion that activation and blockade of the GABA B receptor may result in similar in-vivo effects.…”

Section: Discussionmentioning

confidence: 54%

Blockade of the GABAB receptor suppressed alcohol self-administration in rats: an effect similar to that produced by GABAB receptor activation

Maccioni

Lorrai

Carai

et al. 2022

Behavioural Pharmacology

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Literature data suggest that activation and blockade of the GABA B receptor may produce similar effects on several reward-related behaviours. Accordingly, the present study was designed to investigate whether treatment with the GABA B receptor antagonist, SCH 50911, reproduced the suppressing effect of the GABA B receptor agonist, baclofen, and several positive allosteric modulators of the GABA B receptor on operant oral alcohol self-administration in rats. To this end, Sardinian alcohol-preferring (sP) rats were trained to lever-respond for alcohol (15% v/v) under the fixed ratio (FR) 4 (FR4) schedule of reinforcement. Once lever-responding had stabilized, rats were exposed to test sessions preceded by treatment with SCH 50911 (0, 25, 50, and 100 mg/ kg; i.p.). Two independent experiments were conducted, differing solely in the set of rats used. Selectivity of SCH 50911 effect on alcohol self-administration was assessed by evaluating the effect of SCH 50911 (0, 25, 50, and 100 mg/kg; i.p.) on self-administration of a sucrose solution (0.7% w/v) in sP rats exposed to the FR4 schedule. In both 'alcohol' experiments, treatment with SCH 50911 reduced lever-responding for alcohol and amount of self-administered alcohol. SCH 50911 effect was characterized by large interindividual variability, with several instances of dose-unrelated reductions, and frequent occurrence of complete suppression of leverresponding for alcohol. Similar data were collected in the 'sucrose' experiment. These results extend to alcohol self-administration with the notion that activation and blockade of GABA B receptor may produce unidirectional effects on reward-related behaviours; these similarities are discussed in terms of differential contribution of pre-and postsynaptic GABA B receptors. Behavioural

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Section: Discussionmentioning

confidence: 54%

Blockade of the GABAB receptor suppressed alcohol self-administration in rats: an effect similar to that produced by GABAB receptor activation

Maccioni

Lorrai

Carai

et al. 2022

Behavioural Pharmacology

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“…The therapeutic effect of baclofen in patients with alcohol use disorder is not completely understood, but likely involves two pathways. Baclofen impacts the regulation of emotional behavior through activation of GABA-B receptors in the limbic system, which leads to improved control of anxiety, a frequent comorbidity of alcohol use disorder ( Addolorato et al, 2009 ; Holtyn and Weerts, 2022 ). Due to the ability of GABA-B receptor agonists and GABA-B receptor allosteric modulators to downregulate the neuronal stress circuit, these medications have been investigated for therapeutic use in stress-related psychiatric disorders including anxiety, mood-disturbances and alcohol use disorder ( Morley et al, 2014 ; Felice et al, 2022 ).…”

Section: Off-label Medication For Relapse Prophylaxismentioning

confidence: 99%

Off-label and investigational drugs in the treatment of alcohol use disorder: A critical review

Fischler

Soyka²,

Seifritz³

et al. 2022

Front. Pharmacol.

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Compounds known to be successful in the treatment of alcohol use disorder include the aversive agent, Disulfiram, the glutamatergic NMDA receptor antagonist, Acamprosate, and the opioid receptor antagonists, Naltrexone and Nalmefene. Although all four are effective in maintaining abstinence or reduction of alcohol consumption, only a small percentage of patients receive pharmacological treatment. In addition, many other medications have been investigated for their therapeutic potential in the treatment of alcohol use disorder. In this review we summarize and compare Baclofen, Gabapentin, Topiramate, Ondansetron, Varenicline, Aripiprazole, Quetiapine, Clozapine, Antidepressants, Lithium, Neuropeptide Y, Neuropeptide S, Corticotropin-releasing factor antagonists, Oxytocin, PF-05190457, Memantine, Ifenprodil, Samidorphan, Ondelopran, ABT-436, SSR149415, Mifepristone, Ibudilast, Citicoline, Rimonabant, Surinabant, AM4113 and Gamma-hydroxybutyrate While some have shown promising results in the treatment of alcohol use disorder, others have disappointed and should be excluded from further investigation. Here we discuss the most promising results and highlight medications that deserve further preclinical or clinical study. Effective, patient-tailored treatment will require greater understanding provided by many more preclinical and clinical studies.

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“…Results with GABA B activation in animal models of alcohol addiction were recently reviewed (Holtyn & Weerts, 2020). In brief, much of the data have been obtained with baclofen, a selective GABA B receptor agonist that for more than four decades has been clinically approved as a treatment for muscle spasticity.…”

Section: Role Of Gaba B Receptors In Alcohol Seekingmentioning

confidence: 99%

“…PAMs of the GABA B receptor have the potential to avoid these effects, by targeting a site that is topographically distinct from the orthosteric GABA binding sites, and instead potentiating the effect of GABA upon its binding to the receptor (Froestl, 2010;Perdona et al, 2011). GABA B PAMs have received considerable interest as potential therapeutics for alcohol addiction in recent years (Augier, 2021;Holtyn & Weerts, 2020;.…”

Section: Role Of Gaba B Receptors In Alcohol Seekingmentioning

confidence: 99%

Neurobiology of alcohol seeking behavior

Domi

Adermark

et al. 2021

Journal of Neurochemistry

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A main challenge of addiction treatment is to prevent relapse after patients achieve abstinence. Half a century ago, it was reported that more than 50% of newly abstinent patients with alcohol addiction (hereafter equated with alcoholism, alcohol dependence, or moderate -severe alcohol use disorder) relapse within three months (Hunt et al., 1971). Disappointingly, these numbers have remained largely unchanged over time (Sinha, 2011). In people suffering from alcohol addiction, stressful events, drug-associated cues and contexts, or re-exposure to a small amount of alcohol ("priming", or "the first drink") trigger a chain of behaviors that frequently culminates in relapse (Brownell et al., 1986;Hendershot et al., 2011). An urge to drink, or "craving", is often (but not always) an antecedent of relapse (Wray et al., 2014). Its causal role for initiating substance use has long been debated (Tiffany, 1990), but research has shown that the magnitude of craving in response to triggers, assessed under controlled laboratory conditions, reliably

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GABAB Receptors and Alcohol Use Disorders: Preclinical Studies

Cited by 23 publications

References 97 publications

Blockade of the GABAB receptor suppressed alcohol self-administration in rats: an effect similar to that produced by GABAB receptor activation

Blockade of the GABAB receptor suppressed alcohol self-administration in rats: an effect similar to that produced by GABAB receptor activation

Off-label and investigational drugs in the treatment of alcohol use disorder: A critical review

Neurobiology of alcohol seeking behavior

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